PROJECT SUMMARY/ABSTRACT Hepatitis C virus (HCV) chronically infects 2-3% of the global population, predisposing the patients to chronic liver diseases and liver cancer. A broadly effective vaccine will be a cost- effective mean to solve this global problem. However, HCV is genetically varied and vaccines designed based on a single viral strain will not be effectively against genetically diverse circulating viruses. To overcome this scientific challenge, the vaccine candidates must target conserved regions on the virus. The goal of this application is to determine the molecular structure of virus neutralizing epitopes to aid the rational design of immunogens, that will focus antibody responses to the conserved epitopes in vaccination. This epitope vaccine approach include: (1) Determination of crystal structures of HCV antibody epitopes in complex with the corresponding broadly neutralizing antibodies; (2) Design and synthesis of immunogens as biomimetics of the known epitope structures; (3) Testing of the novel immunogens in a small animal model of HCV infection to identify lead vaccine candidates. If successful, this proposal can result in novel HCV vaccine candidates for clinical trials, and also significantly advance the HCV and vaccine fields.